Aldose reductase inhibitors and methods of use thereof

ABSTRACT

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, the treatment of ischemic injury, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, infections of the skin, peripheral vascular disease, stroke, asthma, and the like.

This application is a continuation of U.S. patent application Ser. No.15/961,288, filed Apr. 24, 2018, which is a continuation ofInternational Application PCT/US2017/038505, filed Jun. 21, 2017, whichclaims the benefit of U.S. Provisional Application No. 62/352,784, filedJun. 21, 2016, the entire contents of which are hereby incorporated byreference in its entirety.

All patents, patent applications and publications cited herein arehereby incorporated by reference in their entirety. The disclosures ofthese publications in their entireties are hereby incorporated byreference into this application in order to more fully describe thestate of the art as known to those skilled therein as of the date of theinvention described and claimed herein.

This patent disclosure contains material that is subject to copyrightprotection. The copyright owner has no objection to the facsimilereproduction by anyone of the patent document or the patent disclosureas it appears in the U.S. Patent and Trademark Office patent file orrecords, but otherwise reserves any and all copyright rights.

FIELD OF THE INVENTION

The present invention relates to novel compounds and pharmaceuticalcompositions thereof, and methods for promoting healthy aging of skin,the treatment of skin disorders, the treatment of cardiovasculardisorders, the treatment of renal disorders, the treatment ofangiogenesis disorders, such as cancer, treatment of tissue damage, suchas non-cardiac tissue damage, the treatment of evolving myocardialinfarction, the treatment of ischemic injury, and the treatment ofvarious other disorders, such as complications arising from diabeteswith the compounds and compositions of the invention. Other disorderscan include, but are not limited to, atherosclerosis, coronary arterydisease, diabetic nephropathy, diabetic neuropathy, diabeticretinopathy, diabetic cardiomyopathy, infections of the skin, peripheralvascular disease, stroke, asthma, and the like.

BACKGROUND OF THE INVENTION

Diabetes is one of the most common chronic disorders, in which highblood glucose levels result from a lack of insulin production and/orinsulin sensitivity. Individuals with high blood glucose metabolize moreglucose via a glucose to sorbitol to fructose pathway in insulininsensitive cells such as lenses, peripheral nerves and glomerulus. Thisleads to an overabundance of sorbitol in the cells, which is not easilydiffused through the cell membrane. The increased concentration ofsorbitol triggers an influx of water into the cells, causing swellingand potential damage.

Aldose reductase (AR) is a monomeric, NADPH-dependent oxidoreductasefrom the aldo-keto reductase family of enzymes. It is an enzyme that ispresent in many parts of the body. Aldose reductase catalyzes thereduction of saturated and unsaturated aldehydes, including aldo sugarsand monosaccharides, as well as a broad array of other substrates.Primarily, aldose reductase catalyzes the reduction of glucose tosorbitol, one of the steps in the sorbitol pathway that is responsiblefor fructose formation from glucose. Aldose reductase activity increasesas the glucose concentration rises in diabetic conditions where tissuesare no longer insulin sensitive. These tissues include, for example,lenses, peripheral nerves and glomerulus of the kidney. Sorbitol cannoteasily diffuse through cell membranes and therefore accumulates, causingosmotic damage, which in turn leads to retinopathy, neuropathy,nephropathy, and cardiomyopathy. The mechanism of damage also occursthrough increased oxidative stress and damage, and an increased amountof advanced glycation endproducts. Therefore, inhibition of aldosereductase could prevent the buildup of sorbitol in insulin insensitivecells in diabetics, and presents a novel method to prevent themacrovascular and microvascular complications in diabetic patients. Inaddition, aldose reductase inhibitors, such as zopolrestat, may aid intreating or ameliorating such effects and have shown efficacy in woundhealing in the corneal epithelium of diabetic animal models. Lastly, ARhas recently been implicated in a wide range of therapeutic areasincluding cancer, myocardial infarction and ischemic injury, asthma, andtransplantation.

Previous clinical trials have shown that while aldose reductaseinhibitors are well tolerated by patients, they are minimally effectivein combating disease. These failures have been attributed to the currentaldose reductase inhibitors possessing poor activity and shorthalf-life, resulting in decreased efficacy. Additionally, some aldosereductase inhibitors are toxic. Thus, there is a need for new aldosereductase inhibitor compounds.

SUMMARY

It is understood that any of the embodiments described below can becombined in any desired way, and that any embodiment or combination ofembodiments can be applied to each of the aspects described below,unless the context indicates otherwise.

In one aspect, the invention provides a compound of Formula (I)

wherein,

R¹ is CO₂R² or CO₂ ⁻X⁺;

R² is H, (C₁-C₆)-alkyl, (C₁-C₆)-hydroxyalkyl, or (C₁-C₆)-aminoalkyl;

X¹ is H or halogen;

X² is H or halogen;

Y is a bond, C═O, C═S, C═NH, or C═N(C₁-C₄)-alkyl;

Z is

A¹ is NR⁷, O, S or CH₂;

A² is N or CH;

A³ is NR⁷, O, or S;

R³ through R⁶ are independently hydrogen, halogen, cyano, acyl,haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio, (C₁-C₄)-alkylsulfinyl, or(C₁-C₄)-alkylsulfonyl;

R⁷ is hydrogen, C₁-C₄ alkyl, or C(O)O—(C₁-C₄)-alkyl; and

X⁺ is a counter ion; or a pharmaceutically acceptable salt or solvatethereof.

In some embodiments, R² is hydrogen or (C₁-C₆)-alkyl;

Y is C═O;

A¹ is NR⁷, O, or S;

A² is N;

A³ is O, or S; and

R³ through R⁶ are independently hydrogen, halogen, cyano, acyl,haloalkyl, haloalkoxy, haloalkylthio, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy,(C₁-C₄)-alkylthio, (C₁-C₄)-alkylsulfinyl, or (C₁-C₄)-alkylsulfonyl;

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, R² is hydrogen or tert-butyl;

R³ through R⁶ are independently hydrogen, halogen, or haloalkyl; and

R⁷ is hydrogen, (C₁-C₄)-alkyl, or C(O)O-tert-butyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, Z is

In some embodiments, R² is hydrogen or (C₁-C₆)-alkyl;

Y is C═O;

A¹ is NR⁷, O, or S;

A² is N;

R³ through R⁶ are independently hydrogen, halogen, cyano, acyl,haloalkyl, haloalkoxy, haloalkylthio, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy,(C₁-C₄)-alkylthio, (C₁-C₄)-alkylsulfinyl, or (C₁-C₄)-alkylsulfonyl; and

R⁷ is hydrogen, C₁-C₄ alkyl, or C(O)O—(C₁-C₄)-alkyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, R² is hydrogen or tert-butyl;

Y is C═O;

A¹ is NR⁷, O or S;

A² is N;

R³ through R⁶ are independently hydrogen, halogen, or haloalkyl; and

R⁷ is hydrogen, (C₁-C₄)-alkyl, or C(O)O-tert-butyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, R² is hydrogen or tert-butyl;

Y is C═O;

A¹ is NR⁷, O or S;

A² is N;

R³ through R⁶ are independently hydrogen, halogen, or CF₃; and

R⁷ is hydrogen, (C₁-C₄)-alkyl, or C(O)O-tert-butyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, R² is hydrogen;

X¹ is H;

X² is H;

Y is C═O;

A¹ is S;

A² is N;

R³ through R⁶ are independently hydrogen, halogen, or haloalkyl; and

R⁷ is hydrogen, (C₁-C₄)-alkyl, or C(O)O-tert-butyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, R² is hydrogen;

X¹ is H;

X² is H;

Y is C═O;

A¹ is S;

A² is N;

R³, R⁵, and R⁶ are hydrogen;

R⁴ is hydrogen, halogen, or haloalkyl; and

R⁷ is hydrogen, (C₁-C₄)-alkyl, or C(O)O-tert-butyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound of Formula (I) is represented by theformula

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, R² is hydrogen;

X¹ is Cl;

X² is Cl;

Y is C═O;

A¹ is S;

A² is N;

R³ through R⁶ are independently hydrogen, halogen, or haloalkyl; and

R⁷ is hydrogen, (C₁-C₄)-alkyl, or C(O)O-tert-butyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, R² is hydrogen;

X¹ is Cl;

X² is Cl;

Y is C═O;

A¹ is S;

A² is N;

R³, R⁵, and R⁶ are hydrogen;

R⁴ is hydrogen, halogen, or haloalkyl; and

R⁷ is hydrogen, (C₁-C₄)-alkyl, or C(O)O-tert-butyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound of Formula (I) is represented by theformula

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, Z is

In some embodiments, R² is hydrogen or (C₁-C₆)-alkyl;

Y is C═O;

R³ through R⁶ are independently hydrogen, halogen, cyano, acyl,haloalkyl, haloalkoxy, haloalkylthio, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy,(C₁-C₄)-alkylthio, (C₁-C₄)-alkylsulfinyl, or (C₁-C₄)-alkylsulfonyl; and

R⁷ is hydrogen, C₁-C₄ alkyl, or C(O)O—(C₁-C₄)-alkyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, R² is hydrogen or tert-butyl;

Y is C═O;

R³ through R⁶ are independently hydrogen, halogen, or haloalkyl; and

R⁷ is hydrogen, (C₁-C₄)-alkyl, or C(O)O-tert-butyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, R² is hydrogen or tert-butyl;

Y is C═O;

R³ through R⁶ are independently hydrogen or halogen; and

R⁷ is hydrogen, (C₁-C₄)-alkyl, or C(O)O-tert-butyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, R² is hydrogen;

X¹ is H;

X² is H;

Y is C═O;

R³ through R⁶ are independently hydrogen, halogen, or haloalkyl; and

R⁷ is hydrogen, (C₁-C₄)-alkyl, or C(O)O-tert-butyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, R² is hydrogen;

X¹ is H;

X² is H;

Y is C═O;

R³, R⁵, and R⁶ are hydrogen;

R⁴ is hydrogen or halogen; and

R⁷ is hydrogen, (C₁-C₄)-alkyl, or C(O)O-tert-butyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound of Formula (I) is represented by theformula

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, R² is hydrogen;

X¹ is Cl;

X² is Cl;

Y is C═O;

R³ through R⁶ are independently hydrogen, halogen, or haloalkyl; and

R⁷ is hydrogen, (C₁-C₄)-alkyl, or C(O)O-tert-butyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, R² is hydrogen;

X¹ is Cl;

X² is Cl;

Y is C═O;

A³ is NR⁷, O or S; and

R³, R⁵, and R⁶ are hydrogen;

R⁴ is hydrogen or halogen; and

R⁷ is hydrogen, (C₁-C₄)-alkyl, or C(O)O-tert-butyl; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound of Formula (I) is selected from thegroup consisting of:

In some embodiments, the counter ion is selected from the groupconsisting of: sodium, lithium, potassium, calcium, magnesium, zinc,ammonium, and tetrafluoroborate.

In some embodiments, the counter ion is selected from the groupconsisting of:

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of Formula (I) and a pharmaceutically acceptablecarrier.

In another aspect, the invention provides a method of inhibiting aldosereductase activity in a subject comprising administration of atherapeutically effective amount of a compound of Formula (I) to asubject in need thereof.

In some embodiments, the subject is diabetic.

In some embodiments, the subject is a human.

In another aspect, the invention provides a method of treating adisorder in a subject comprising administration of a therapeuticallyeffective amount of a compound of Formula (I) to a subject in needthereof.

In some embodiments, the disorder is atherosclerosis.

In some embodiments, the disorder is diabetic nephropathy.

In some embodiments, the disorder is diabetic neuropathy.

In some embodiments, the disorder is diabetic retinopathy.

In some embodiments, the disorder is a cardiovascular disease.

In some embodiments, the disorder is peripheral vascular disease.

In some embodiments, the disorder is an angiogenesis disorder.

In some embodiments, the disorder is tissue damage.

In some embodiments, the disorder is diabetic cardiomyopathy.

In another aspect, the invention provides a method to treat a skindisorder or promote healthy aging of skin, comprising applying to adermal substrate a therapeutically effective amount of a compound ofFormula (I), or a pharmaceutical composition comprising a compound ofFormula (I) and a pharmaceutically acceptable carrier, to a subject inneed thereof.

In some embodiments, the dermal substrate is human skin.

In another aspect, the invention provides a method of treating a subjectwith evolving myocardial infarction comprising: administering atherapeutically effective amount of a compound of Formula (I), or apharmaceutical composition comprising a compound of Formula (I) and apharmaceutically acceptable carrier, to a subject in need thereof.

The present invention is based, in part, on certain discoveries whichare described more fully in the Examples section of the presentapplication. For example, the present invention is based, in part, onthe discovery of compounds of formula (I) and the aldose reductaseinhibition exhibited by such compounds.

These and other embodiments of the invention are further described inthe following sections of the application, including the DetailedDescription, Examples, and Claims. Still other objects and advantages ofthe invention will become apparent by those of skill in the art from thedisclosure herein, which are simply illustrative and not restrictive.Thus, other embodiments will be recognized by the ordinarily skilledartisan without departing from the spirit and scope of the invention.

DETAILED DESCRIPTION

Aldose reductase inhibitors are described, for example, in U.S. Pat.Nos. 8,916,563; 5,677,342; 5,304,557; 5,155,259; 4,954,629; 4,939,140;U.S. Publication Number US 2006/0293265; Roy et al., in DiabetesResearch and Clinical Practice 1990, 10(1), 91-97; CN101143868A; andChatzopoulou et al., in Expert Opin. Ther. Pat. 2012, 22, 1303; andreferences cited therein; each of which hereby incorporated by referencein its entirety. Aldose reductase inhibitors include, for example,zopolrestat, epalrestat, ranirestat, berberine and sorbinil. A novelfamily of aldose reductase inhibitors has been discovered and isdescribed herein. Surprisingly, this novel family comprises compoundsthat exhibit dramatically improved properties such as, for example,binding affinity, solubility, and polarity relative to other aldosereductase inhibitors such as, for example, zopolrestat. Compounds suchas zopolrestat are described, for example in U.S. Pat. Nos. 4,939,140;6,159,976; and 6,570,013; each of which hereby incorporated by referencein its entirety.

The compounds and/or compositions of the invention may be effective intreating, reducing, and/or suppressing complications related to aldosereductase activity such as, for example, atherosclerosis, neuropathy,retinopathy, nephropathy, cardiomyopathy, and multiple complications indiabetic patients. The compounds and/or compositions of the inventionmay also be effective in treating, reducing, and/or reducingcardiovascular and renal disorders in non-diabetic patients, as well aspromoting healthy aging of skin or wound healing. Treatment using aldosereductase inhibitors is described in, e.g., CN102512407A;WO2008002678A2; CN101143868A; Srivastava et al., in Chem Biol Interact.2011, 30, 330; Hu et al., in PLoS One 2014, 9(2), e87096; Satoh et al.,in J Diabetes Res. 2016, 2016, U.S. Pat. No. 5,383,797; Chatzopoulou etal., in Expert Opin. Ther. Pat. 2012, 22, 1303; each of which is herebyincorporated by reference in its entirety.

Abbreviations and Definitions

The term “aldose reductase inhibitor” refers to compounds and salts orsolvates thereof that function by inhibiting the activity of the enzymealdose reductase, which is primarily responsible for regulatingmetabolic reduction of aldoses. Exemplary aldoses include, but are notlimited to, glucose or galactose, and their corresponding polyols, suchas sorbitols and galactitols. Exemplary aldose reductase inhibitors maybe found in U.S. Pat. Nos. 8,916,563; 5,677,342; 5,304,557; 5,155,259;4,954,629; 4,939,140; U.S. Publication Number US 2006/0293265; and Royet al., in Diabetes Research and Clinical Practice 1990, 10(1), 91-97;and each of which hereby incorporated by reference in its entirety.

The term “compound of the invention” as used herein means a compound offormula (I). The term is also intended to encompass salts, hydrates,pro-drugs and solvates thereof.

The term “composition(s) of the invention” as used herein meanscompositions comprising a compound of the invention, and salts,hydrates, pro-drugs, or solvates thereof. The compositions of theinvention may further comprise other agents such as, for example,excipients, stabilants, lubricants, solvents, and the like.

The term “alkyl”, as used herein, unless otherwise indicated, refers toa monovalent aliphatic hydrocarbon radical having a straight chain,branched chain, monocyclic moiety, or polycyclic moiety or combinationsthereof, wherein the radical is optionally substituted at one or morecarbons of the straight chain, branched chain, monocyclic moiety, orpolycyclic moiety or combinations thereof with one or more substituentsat each carbon, where the one or more substituents are independentlyC₁-C₁₀ alkyl. Examples of “alkyl” groups include methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl,heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,norbornyl, and the like.

The term “solvate” as used herein means a compound, or apharmaceutically acceptable salt thereof, wherein molecules of asuitable solvent are incorporated in the crystal lattice. A suitablesolvent is physiologically tolerable at the dosage administered.Examples of suitable solvents are ethanol, water and the like. Whenwater is the solvent, the molecule is referred to as a “hydrate.”

The term “pharmaceutically acceptable salt” is intended to include saltsderived from inorganic or organic acids including, for examplehydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric,formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic,salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic,trifluroacetic, trichloroacetic, naphthalene-2 sulfonic and other acids;and salts derived from inorganic or organic bases including, for examplesodium, potassium, calcium, magnesium, zinc, ammonia, lysine, arginine,histidine, polyhydroxylated amines or tetrafluoroborate. Exemplarypharmaceutically acceptable salts are found, for example, in Berge, etal. (J. Pharm. Sci. 1977, 66(1), 1; and U.S. Pat. Nos. 6,570,013 and4,939,140; (each hereby incorporated by reference in its entirety).Pharmaceutically acceptable salts are also intended to encompasshemi-salts, wherein the ratio of compound:acid is respectively 2:1.Exemplary hemi-salts are those salts derived from acids comprising twocarboxylic acid groups, such as malic acid, fumaric acid, maleic acid,succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acidand citric acid. Other exemplary hemi-salts are those salts derived fromdiprotic mineral acids such as sulfuric acid. Exemplary preferredhemi-salts include, but are not limited to, hemimaleate, hemifumarate,and hemisuccinate.

The term “acid” contemplates all pharmaceutically acceptable inorganicor organic acids. Inorganic acids include mineral acids such ashydrohalic acids, such as hydrobromic and hydrochloric acids, sulfuricacids, phosphoric acids and nitric acids. Organic acids include allpharmaceutically acceptable aliphatic, alicyclic and aromatic carboxylicacids, dicarboxylic acids, tricarboxylic acids, and fatty acids.Preferred acids are straight chain or branched, saturated or unsaturatedC1-C20 aliphatic carboxylic acids, which are optionally substituted byhalogen or by hydroxyl groups, or C6-C12 aromatic carboxylic acids.Examples of such acids are carbonic acid, formic acid, fumaric acid,acetic acid, propionic acid, isopropionic acid, valeric acid,alpha-hydroxy acids, such as glycolic acid and lactic acid, chloroaceticacid, benzoic acid, methane sulfonic acid, and salicylic acid. Examplesof dicarboxylic acids include oxalic acid, malic acid, succinic acid,tataric acid and maleic acid. An example of a tricarboxylic acid iscitric acid. Fatty acids include all pharmaceutically acceptablesaturated or unsaturated aliphatic or aromatic carboxylic acids having 4to 24 carbon atoms. Examples include butyric acid, isobutyric acid,sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid,linoleic acid, linolenic acid, and phenylsteric acid. Other acidsinclude gluconic acid, glycoheptonic acid and lactobionic acid.

As used herein the term “about” is used herein to mean approximately,roughly, around, or in the region of. When the term “about” is used inconjunction with a numerical range, it modifies that range by extendingthe boundaries above and below the numerical values set forth. Ingeneral, the term “about” is used herein to modify a numerical valueabove and below the stated value by a variance of 20 percent up or down(higher or lower).

An “effective amount”, “sufficient amount” or “therapeutically effectiveamount” as used herein is an amount of a compound that is sufficient toeffect beneficial or desired results, including clinical results. Assuch, the effective amount may be sufficient, for example, to reduce orameliorate the severity and/or duration of afflictions related to aldosereductase, or one or more symptoms thereof, prevent the advancement ofconditions or symptoms related to afflictions related to aldosereductase, or enhance or otherwise improve the prophylactic ortherapeutic effect(s) of another therapy. An effective amount alsoincludes the amount of the compound that avoids or substantiallyattenuates undesirable side effects.

As used herein and as well understood in the art, “treatment” is anapproach for obtaining beneficial or desired results, including clinicalresults. Beneficial or desired clinical results may include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions, diminution of extent of disease or affliction, a stabilized(i.e., not worsening) state of disease or affliction, preventing spreadof disease or affliction, delay or slowing of disease or afflictionprogression, amelioration or palliation of the disease or afflictionstate and remission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment.

The phrase “in need thereof” refers to the need for symptomatic orasymptomatic relief from conditions related to aldose reductase activityor that may otherwise be relieved by the compounds and/or compositionsof the invention.

In one embodiment, aldose reductase inhibitors described hereinencompass compounds of Formula (I) or pharmaceutically acceptable salts,pro-drugs and solvates thereof,

wherein,

R¹ is CO₂R² or CO₂ ⁻X⁺;

R² is H, (C₁-C₆)-alkyl, (C₁-C₆)-hydroxyalkyl, or (C₁-C₆)-aminoalkyl;

X¹ is H or halogen;

X² is H or halogen;

Y is a bond, C═O, C═S, C═NH, or C═N(C₁-C₄)-alkyl;

Z is

A¹ is NR⁷, O, S or CH₂;

A² is N or CH;

A³ is NR⁷, O, or S;

R³ through R⁶ are independently hydrogen, halogen, cyano, acyl,haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio, (C₁-C₄)-alkylsulfinyl, or(C₁-C₄)-alkylsulfonyl;

R⁷ is hydrogen, C₁-C₄ alkyl, or C(O)O—(C₁-C₄)-alkyl; and

X⁺ is a counter ion.

It will be recognized by those of skill in the art that the designationof

Z is

or Z is

indicates that when Z is

the compounds of Formula (I) are understood to encompass

and when Z is

the compounds of Formula (I) are understood to encompass

In certain embodiments, R¹ is CO₂R² or CO₂ ⁻X⁺. In certain embodiments,R¹ is CO₂R². In certain embodiments, R¹ is CO₂ ⁻X⁺.

In certain embodiments, R² is hydrogen or (C₁-C₆)-alkyl. In certainembodiments, R² is hydrogen or (C₁-C₄)-alkyl. In certain embodiments, R²is hydrogen or (C₁-C₃)-alkyl. In certain embodiments, R² is hydrogen,methyl, or ethyl. In certain embodiments, R² is hydrogen or methyl. Incertain embodiments, R² is methyl or ethyl. In certain embodiments, R²is methyl. In certain embodiments, R² is hydrogen. In certainembodiments, R² is (C₁-C₆)-alkyl. In certain embodiments, R² is(C₁-C₆)-n-alkyl. In certain embodiments, R² is (C₁-C₂)-alkyl. In certainembodiments, R² is (C₁-C₃)-alkyl. In certain embodiments, R² is(C₁-C₄)-alkyl. In certain embodiments, R² is tert-butyl.

In certain embodiments, R³ through R⁶ are independently hydrogen,halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio,trifluoroacetyl, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio,(C₁-C₄)-alkylsulfinyl, or (C₁-C₄)-alkylsulfonyl.

In certain embodiments, R³ through R⁶ are independently hydrogen,halogen or haloalkyl. In certain embodiments, R³ through R⁶ areindependently hydrogen, halogen or trihaloalkyl.

In certain embodiments, R³ and R⁶ are hydrogen. In certain embodiments,R³, R⁵, and R⁶ are hydrogen.

In certain embodiments, R⁴ is hydrogen, halogen or haloalkyl. In certainembodiments, R⁴ is hydrogen. In certain embodiments, R⁴ is halogen. Incertain embodiments, R⁴ is haloalkyl. In certain embodiments, R⁴ is CF₃.

In certain embodiments, R³ through R⁶ are hydrogen. In certainembodiments, R³, R⁵, R⁶ are hydrogen and R⁴ is halogen or haloalkyl. Incertain embodiments, R³, R⁵, R⁶ are hydrogen and R⁴ is haloalkyl. Incertain embodiments, R³, R⁵, R⁶ are hydrogen and R⁴ is CF₃. In certainembodiments, R³, R⁵, R⁶ are hydrogen and R⁴ is halogen. In certainembodiments, R³, R⁵, R⁶ are hydrogen and R⁴ is F. In certainembodiments, R³, R⁵, R⁶ are hydrogen and R⁴ is Cl.

In certain embodiments, Y is C═O, C═S, C═NH, or C═N(C₁-C₄)-alkyl. Incertain embodiments, Y is C═O or C═S. In certain embodiments, Y is C═O.In certain embodiments, Y is C═S. In certain embodiments, Y is C═NH, orC═N(C₁-C₄)-alkyl.

In certain embodiments, A¹ is NR⁷, O, S or CH₂. In certain embodiments,A¹ is NR⁷, O, or S. In certain embodiments, A¹ is NR⁷, S or CH₂. Incertain embodiments, A¹ is NR⁷ or O. In certain embodiments, A¹ is NR⁷or S. In certain embodiments, A¹ is NR⁷. In certain embodiments, A¹ isO. In certain embodiments, A¹ is S.

In certain embodiments, A² is N or CH. In certain embodiments, A² is N.In certain embodiments, A² is CH.

In certain embodiments, A³ is NR⁷, O, or S. In certain embodiments, A³is O. In certain embodiments, A³ is S. In certain embodiments, A³ isNR⁷.

In certain embodiments, X¹ and X² are hydrogen.

In certain embodiments, X¹ and X² are halogen. In certain embodiments,X¹ and X² are Cl.

In certain embodiments, X¹ and X² are independently hydrogen or halogen.In certain embodiments, X¹ is hydrogen and X² is Cl. In certainembodiments, X¹ is Cl and X² is hydrogen.

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, R⁷ is hydrogen, C₁-C₄ alkyl, orC(O)O—(C₁-C₄)-alkyl. In certain embodiments, R⁷ is hydrogen. In certainembodiments, R⁷ is C₁-C₄ alkyl. In certain embodiments, R⁷ is C₁-C₃alkyl. In certain embodiments, R⁷ is C₁-C₂ alkyl. In certainembodiments, R⁷ is C₁-C₄ n-alkyl. In certain embodiments, R⁷ is C₁-C₃n-alkyl. In certain embodiments, R⁷ is C(O)O—(C₁-C₄)-alkyl. In certainembodiments, R⁷ is C(O)O—(C₁-C₃)-alkyl. In certain embodiments, R⁷ isC(O)O—(C₁-C₂)-alkyl. In certain embodiments, R⁷ isC(O)O—(C₁-C₄)-n-alkyl. In certain embodiments, R⁷ isC(O)O—(C₁-C₃)-n-alkyl.

In certain embodiments, R¹ is CO₂R²;

R² is H or (C₁-C₆)-alkyl;

X¹ is H;

X² is H;

Y is C═O;

Z is

A¹ is NR⁷, O, or S;

A² is N;

A³ is O or S;

R³ through R⁶ are independently hydrogen, halogen, cyano, acyl,haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio, (C₁-C₄)-alkylsulfinyl, or(C₁-C₄)-alkylsulfonyl; and

R⁷ is hydrogen, C₁-C₄ alkyl, or C(O)O—(C₁-C₄)-alkyl.

In certain embodiments, R¹ is CO₂R²;

R² is H or tert-butyl;

X¹ is H;

X² is H;

Y is C═O;

Z is

A¹ is NR⁷, O, or S;

A² is N;

A³ is O or S;

R⁶ through R⁶ are independently hydrogen, halogen, haloalkyl; and

R⁷ is hydrogen, C₁-C₄ alkyl, or C(O)O—(C₁-C₄)-alkyl.

In certain embodiments, R¹ is CO₂R²;

R² is H or tert-butyl;

X¹ is H;

X² is H;

Y is C═O;

Z is

A¹ is NR⁷, O, or S;

A² is N;

A³ is O or S;

R³, R⁵, and R⁶ are hydrogen;

R⁴ is hydrogen, halogen, or haloalkyl; and

R⁷ is hydrogen, C₁-C₄ alkyl, or C(O)O—(C₁-C₄)-alkyl.

In certain embodiments, R¹ is CO₂R²;

R² is H or (C₁-C₆)-alkyl;

X¹ is halogen;

X² is halogen;

Y is C═O;

Z is

A¹ is NR⁷, O, or S;

A² is N;

A³ is O or S;

R³ through R⁶ are independently hydrogen, halogen, cyano, acyl,haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio, (C₁-C₄)-alkylsulfinyl, or(C₁-C₄)-alkylsulfonyl; and

R⁷ is hydrogen, C₁-C₄ alkyl, or C(O)O—(C₁-C₄)-alkyl.

In certain embodiments, R¹ is CO₂R²;

R² is H or tert-butyl;

X¹ is halogen;

X² is halogen;

Y is C═O;

Z is

A¹ is NR⁷, O, or S;

A² is N;

A³ is O or S;

R³ through R⁶ are independently hydrogen, halogen, haloalkyl; and

R⁷ is hydrogen, C₁-C₄ alkyl, or C(O)O—(C₁-C₄)-alkyl.

In certain embodiments, R¹ is CO₂R²;

R² is H or tert-butyl;

X¹ is Cl;

X² is Cl;

Y is C═O;

Z is

A¹ is NR⁷, O, or S;

A² is N;

A³ is O or S;

R³ through R⁶ are independently hydrogen, halogen, haloalkyl; and

R⁷ is hydrogen, C₁-C₄ alkyl, or C(O)O—(C₁-C₄)-alkyl.

In certain embodiments, R¹ is CO₂R²;

R² is H or tert-butyl;

X¹ is Cl;

X² is Cl;

Y is C═O;

Z is

A¹ is NR⁷, O, or S;

A² is N;

A³ is O or S;

R³, R⁵, and R⁶ are hydrogen;

R⁴ is hydrogen, halogen, or haloalkyl; and

R⁷ is hydrogen, C₁-C₄ alkyl, or C(O)O—(C₁-C₄)-alkyl.

In certain embodiments, the compound of Formula (I) is selected from thegroup consisting of:

In certain embodiments, the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, X⁺ is a counter ion. In certain embodiments, thecounter ion is sodium, lithium, potassium, calcium, ammonium, ortetrafluoroborate. In certain embodiments, the counter ion is sodium,lithium, potassium, calcium, ammonium, or a protonated amino acid. Incertain embodiments, the counter ion is sodium, lithium, potassium,ammonium, or a protonated amino acid. In certain embodiments, thecounter ion is sodium or ammonium. In certain embodiments, the counterion is lithium or potassium. In certain embodiments, the counter ion issodium, ammonium, or an amino acid. In certain embodiments, the counterion is potassium, ammonium, or an amino acid. In certain embodiments,the counter ion is sodium or calcium. In certain embodiments, thecounter ion is lithium, potassium, or calcium. In certain embodiments,the counter ion is sodium. In certain embodiments, the counter ion islithium. In certain embodiments, the counter ion is potassium. Incertain embodiments, the counter ion is calcium. In certain embodiments,the counter ion is ammonium. In certain embodiments, the counter ion istetrafluoroborate. In some embodiments, the compound of Formula (I) ishighly water soluble when X⁺ is a counter ion. It is well known in theart that highly water soluble medicinal preparations, when administeredorally, result in efficient absorption of such preparations from thegastrointestinal tract into systemic circulation. Another hallmark ofsuch preparations is the rapid rate at which they are absorbed into thesystemic circulation resulting in a high concentration of the activeagent in the blood. Also, water soluble preparations are especiallysuitable for parenteral administration, for example, intravenousadministration.

In certain embodiments, the counter ion is a protonated amino acid or aprotonated aminoglycoside. In certain embodiments, the aminoglycoside isglucosamine, galactosamine, mannosamine, or muramic acid. In certainembodiments, the aminoglycoside is glucosamine, galactosamine, ormannosamine. In certain embodiments, the aminoglycoside is glucosamineor galactosamine. In certain embodiments, the aminoglycoside isglucosamine. In certain embodiments, the aminoglycoside isgalactosamine. In certain embodiments, the amino acid is lysine,arginine, or histidine. In certain embodiments, the amino acid is lysineor arginine. In certain embodiments, the amino acid is lysine. Incertain embodiments, the amino acid is arginine.

In certain embodiments, the counter ion is

In certain embodiments, the counter ion is

In certain embodiments, the counter ion is

In certain embodiments, the counter ion is

In certain embodiments, the counter ion is

In certain embodiments, the counter ion is

In certain embodiments, the counter ion is

In certain embodiments, the counter ion is

Synthesis

The compounds described herein can be prepared according to knownprocesses. Schemes 1-4 represent general synthetic schemes for preparingcompounds of formula (I). These schemes are illustrative and are notmeant to limit the possible techniques one skilled in the art may use toprepare compounds disclosed herein. Different methods will be evident tothose skilled in the art. Various modifications to these methods may beenvisioned by those skilled in the art to achieve similar results tothat of the inventors provided below. For example, optional protectinggroups can be used as described, for example, in Greene et al.,Protective Groups in Organic Synthesis (4^(th) ed. 2006).

The compounds of Formula (I-1) can generally be prepared, for example,according to Scheme 1:

where X¹, X², R¹, A¹, A², R², R³ through R⁷ are defined as above and Qis a halogen, such as Cl, Br, I, and the like, or any other leavinggroup, such as OSO₂Me, OMs, OTs, OTf, and the like.

The compounds of Formula (I-2) can generally be prepared, for example,according to Scheme 2:

where X¹, X², A¹, A², R², R³ through R⁷ are defined as above and Q is ahalogen, such as Cl, Br, I, and the like, or any other leaving group,such as OSO₂Me, OMs, OTs, OTf, and the like.

The compounds of Formula (I-3) can generally be prepared, for example,according to Scheme 3:

where X¹, X², R¹, A¹, A², R², R³ through R⁷ are defined as above and Qis a halogen, such as Cl, Br, I, and the like, or any other leavinggroup, such as OSO₂Me, OMs, OTs, OTf, and the like.

In certain embodiments, the reaction can be carried out in the presenceof a base, such as potassium tert-butoxide, sodium hydride, sodiummethoxide, sodium ethoxide, and the like.

In certain embodiments, the reaction can be carried out using aproticsolvents, such as DMF, THF, NMP, and the like. In certain embodiments,the reaction can be carried out using alcohol solvents, such asmethanol, ethanol, and the like.

In certain embodiments, the reaction can be carried out at temperaturesof between about 5° C. to about 80° C., such as 20° C. to 30° C.

In certain embodiments, the reaction can be subsequently followed byfurther separation and purification steps, such as chromatography (e.g.,flash, HPLC, MPLC, etc.), crystallization, and the like.

The compounds of Formula (I-1) can also generally be prepared accordingto exemplary Scheme 4. Cyclic anhydride 5 is converted to compound 6under acidic methanolysis conditions. Activation of the compound 6,followed by nucleophilic addition and decarboxylation provides ketoester7. Treatment of compound 7 with hydrazine affords cyclized compound 8.Compound 8 is then coupled to compound 2 under basic conditions toprovide a compound of formula 9. Deprotection or hydrolysis of compound9 provides a compound of formula 10.

The compounds of Formula (I-2) can also generally be prepared accordingto Scheme 4, by replacing

Similarly, the compounds of Formula (I-3) can also generally be preparedaccording to Scheme 4, by replacing

Other suitable reactions are possible, such as hydrolysis of thecompound of Formula (I) in to obtain different forms of the compound ofFormula (I-1), (I-2), or (I-3). For example, compounds havingtert-butoxy, methoxy, ethoxy, and the like group as R² can be hydrolyzedby reacting with a suitable reagent, such as trifluoroacetic acid (TFA),HCl, KOH, or the like, to obtain a compound of Formula (I) havinghydrogen as R².

For example, the following exemplary synthesis can be carried outaccording to Scheme 5.

In some other embodiments, where Y is C═O, subsequent reactions can becarried out to replace C═O with C═S or C═N, or the like.

Compounds of Formula (2)

To obtain compounds of Formula (2), different possibilities exist.Compounds of Formula (2) can be synthesized by a variety of differentreactions, such as a condensation reaction as schematically illustratedbelow in Scheme 6. The reaction can be carried out using a variety ofsolvents, such as ethanol, methanol, DMF, AcOH, and the like. Thereaction can be carried out at temperatures of between about 5° C. toabout 80° C., such as, for example, 55° C. to 65° C.

Additional exemplary descriptions regarding synthesis of certaincompounds of Formula (2) are described in J. Med. Chem. (1991), Vol. 34,pp. 108-122; J. Med. Chem. (1992), Vol. 35, No. 3, pp. 457-465; and U.S.Pat. No. 8,916,563; each of which hereby incorporated by reference inits entirety.

Compounds of Formula (1)

To obtain compounds of Formula (1), different possibilities exist. Forexample, compounds of Formula (1) can be synthesized as shown in Scheme7. For example, to obtain a compound of Formula (1) when Y is C═O,reaction of a compound represented by Formula (13) with a reagent thatcauses addition-cyclization reaction, such as hydrazine, can be carriedout as shown in Scheme 7. The reaction can be carried out using avariety of solvents, such as ethanol, methanol, THF, and the like. Thereaction can be carried out at temperatures of between about 20° C. toabout 100° C., such as 60° C. to 80° C.

The compounds of Formula (13) can be obtained, for example, by areaction of an anhydride with a reagent that causes a Wittig reaction,such as (tert-butoxycarbonylmethylene)-triphenylphosphorane, and thelike, as shown in Scheme 8. The reaction can be carried out usingaprotic solvents, such as CH₂Cl₂, THF, 1,4-dioxane, toluene, and thelike. The reaction can be carried out at temperatures of between about20° C. to about 110° C., such as 55° C. to 70° C.

In certain embodiments, reaction of an anhydride, such as compound 15,with a reagent that causes a Wittig reaction can lead to a mixture ofthe particular compounds represented by 16 and 17, as exemplified below(Scheme 9). In such instances, if necessary, the mixture can beseparated and purified to obtain the particular compounds of interest(e.g., compound 16 or 17).

In certain embodiments, the compounds of Formula (13) can be obtained bythe Perkins Reaction, as shown in Scheme 10. The Perkins reaction canemploy KOAc/Ac₂O, as shown in Scheme 10. However, other temperatures andother bases, such as K₂CO₃ and the like can be utilized. Additionaldetails of the Perkins reaction can be found in WO 03/061660, thecontents of which are incorporated by reference herein in its entirety.

The compounds of Formula (14) can be obtained by reaction ofdicarboxylic acid derivative represented by Formula (18) with a suitableanhydride forming reagent, such as dicyclohexylcarbodiimide (DCC) oracetic anhydride, to obtain the compounds of Formula (14) asschematically illustrated below (Scheme 11). The reaction can be carriedout using non-nucleophilic solvents, such as acetic anhydride, THF, andthe like. The reaction can be carried out at temperatures of betweenabout 20° C. to about 100° C., such as 60° C. to 80° C.

The compounds of Formula (14) can also be obtained as described by Ayreset al. in Tetrahedron, 1975, 31, 1755-1760 (hereby incorporated byreference in its entirety). The compounds of Formula (14) can beconverted to compounds of formula (I) by known methods, e.g., asdescribed previously in U.S. Pat. No. 8,916,563 (hereby incorporated byreference in its entirety).

The compounds of Formula (18) can generally be obtained throughcommercial sources, such as Sigma-Aldrich. Alternatively, compounds ofFormula (18) can be obtained by reaction of a suitable precursorrepresented by Formula (19) or Formula (20) with a suitable dicarboxylicacid derivative forming reagent, such as NaMnO₄ and/or NaOH, to obtainthe compounds of Formula (18) as schematically illustrated below(Schemes 12 and 13). The reaction can be carried out using aqueoussolvents, such as water. The reaction can be carried out at temperaturesof between about 50° C. to about 100° C., such as 85° C. to 95° C.

The compounds of Formula (18), where X¹ and X² are Cl, can be obtainedas described by Ayres et al. in Tetrahedron, 1975, 31, 1755-1760 (herebyincorporated by reference in its entirety), as in shown in Scheme 14.Bis-iodination of compound 34 followed by transmetallation andcarboxylation provides compound 36. Other halogenated derivatives canalso be used as starting materials to provide compounds of Formula (18).Subsequent conversion of the di-carboxylic acid functional groups ofcompounds of Formula (18) to form a cyclic anhydride, as describedabove, provides compounds of Formula (14). Compounds of Formula (14) canbe converted to compounds of formula (I) by known methods. Exemplarymethods are described in U.S. Pat. No. 8,916,563 (hereby incorporated byreference in its entirety).

Additional Synthetic Schemes for Compound of Formula (I)

The synthetic schemes described above for preparing compounds of formula(I) are illustrative and are not meant to limit the possible techniquesone skilled in the art may use to prepare compounds disclosed herein.Different methods will be evident to those skilled in the art.Additional reactions can be carried out for the synthesis of additionalembodiments of compounds represented by formula (I).

To obtain compounds of Formula (I) where Y is C═S, the followingsynthesis can be carried out (Scheme 15). Treatment of compound 21 withLawesson's reagent provides the corresponding thiocarbonyl derivative22. Subsequent deprotection or hydrolysis provides compound 23.

To obtain compounds of Formula (I) where Y is C═NR*, wherein R*represents hydrogen or an alkyl substituent for example, the followingsynthesis can be carried out (Scheme 16).

Compounds of Formula (I) where Y is a covalent bond can be prepared asdescribed previously in U.S. Pat. No. 8,916,563.

Other substitutions and modifications are further possible as would beapparent to one of ordinary skill in the art. For example, in Scheme 17,KOH can be utilized in place of NaOH. In Scheme 18 below, KOtBu can beused in place of NaH. Additionally, instead of DMF, NMP or THF can beutilized.

In certain embodiments, the following alternative synthesis can becarried out (Scheme 19).

Compounds or compositions of the invention can be useful in applicationsthat benefit from inhibition of aldose reductase enzymes. Exemplaryutility of aldose reductase inhibition may be found, for example, inU.S. Pat. Nos. 8,916,563; 5,677,342; 5,155,259; 4,939,140; U.S.Publication Number US 2006/0293265; and Roy et al., in Diabetes Researchand Clinical Practice 1990, 10(1), 91-97; and references cited therein;each of which hereby incorporated by reference in its entirety.Inhibition of aldose reductase also has been found to prevent metastasisof colon cancer and mitosis in colon cancer cells (See, for example,Tammali, R. et al., Inhibition of Aldose Reductase Prevents Colon CancerMetastasis, Carcinogenesis 2011, doi: 10.1093/carcin/bgr102; publishedonline: Jun. 3, 2011; Angiogenesis 2011 May; 14(2):209-21; and Mol.Cancer Ther. 2010, April; 9(4): 813-824; each of which herebyincorporated by reference in its entirety).

In certain embodiments, compounds and/or compositions of the inventioncan be useful in promoting healthy aging of skin, the treatment of skindisorders, the treatment of angiogenesis disorders such as cancers,including colon cancer, the treatment of non-cardiac tissue damage, thetreatment of cardiovascular disorders, the treatment of renal disorders,the treatment of evolving myocardial infarction, the treatment ofischemic injury, and the treatment various other disorders, such ascomplications arising from diabetes. Such disorders can include, but arenot limited to, atherosclerosis, coronary artery disease, diabeticnephropathy, diabetic neuropathy, diabetic retinopathy, infections ofthe skin, peripheral vascular disease, stroke, asthma and the like.

In certain embodiments, compounds and/or compositions of the inventioncan be useful in cardiovascular applications. For example, compoundsand/or compositions of the invention can be used to treat patientsundergoing a heart bypass surgery to improve recovery after the surgery.In another example, compounds and/or compositions of the invention canbe used to inhibit or reduce accumulation or rapid onset ofatherosclerotic plaque.

In some other embodiments, compounds and/or compositions of theinvention can be useful in topical applications. For example, compoundsand/or compositions of the invention can be used to retard or reduceskin aging.

In certain embodiments, compounds of Formula (I) can be administered toa subject in need of treatment at dosages ranging from about 0.5 toabout 25 mg/kg body weight of the subject to be treated per day, such asfrom about 1.0 to 10 mg/kg. However, additional variations are withinthe scope of the invention.

The compound of Formula (I) can be administered alone or in combinationwith pharmaceutically acceptable carriers, such as diluents, fillers,aqueous solution, and even organic solvents. The compound and/orcompositions of the invention can be administered as a tablet, powder,lozenge, syrup, injectable solution, and the like. Additionalingredients, such as flavoring, binder, excipients, and the like arewithin the scope of the invention.

In certain embodiments, pharmaceutically acceptable compositions cancontain a compound of Formula (I) and/or a pharmaceutically acceptablesalt thereof at a concentration ranging from about 0.01 to about 2 wt %,such as 0.01 to about 1 wt % or about 0.05 to about 0.5 wt %. Thecomposition can be formulated as a solution, suspension, ointment, or acapsule, and the like. The pharmaceutical composition can be prepared asan aqueous solution and can contain additional components, such aspreservatives, buffers, tonicity agents, antioxidants, stabilizers,viscosity-modifying ingredients and the like.

Other equivalent modes of administration can be found in U.S. Pat. No.4,939,140, hereby incorporated by reference herein in its entirety.

In one embodiment, the present invention provides for the use ofpharmaceutical compositions and/or medicaments comprised of a compoundof Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate,or pro-drug thereof, in a method of treating a disease state, and/orcondition caused by or related to aldose reductase.

In another embodiment, the method of treatment comprises the steps of:(i) identifying a subject in need of such treatment; (ii) providing acompound of Formula (I), or a pharmaceutically acceptable salt, hydrate,solvate, or pro-drug thereof; and (iii) administering said compound ofFormula (I) in a therapeutically effective amount to treat, suppressand/or prevent the disease state or condition in a subject in need ofsuch treatment.

In another embodiment, the method of treatment comprises the steps of:(i) identifying a subject in need of such treatment; (ii) providing acomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, or pro-drug thereof; and (iii)administering said composition in a therapeutically effective amount totreat, suppress and/or prevent the disease state or condition in asubject in need of such treatment.

In one embodiment, the subject in need is an animal. In anotherembodiment, the patient in need is an animal. Animals include allmembers of the animal kingdom, but are not limited to humans, mice,rats, cats, monkeys, dogs, horses, and swine. In some embodiments, thesubject in need is a human. In some embodiments, the subject in need isa mouse, a rat, a cat, a monkey, a dog, a horse, or a pig. In someembodiments, the patient in need is a human. In some embodiments, thepatient in need is a mouse, a rat, a cat, a monkey, a dog, a horse, or apig.

In one embodiment, the compound or composition is administered orally.In another embodiment, the compound or composition is administeredintravenously.

In one embodiment, the methods comprise administering to the subject aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate or pro-drug thereof; or a compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, hydrate or pro-drug thereof, and a pharmaceuticallyacceptable carrier.

Pharmaceutically acceptable carriers are well-known to those skilled inthe art, and include, for example, adjuvants, diluents, excipients,fillers, lubricants and vehicles. In some embodiments, the carrier is adiluent, adjuvant, excipient, or vehicle. In some embodiments, thecarrier is a diluent, adjuvant, or excipient. In some embodiments, thecarrier is a diluent or adjuvant. In some embodiments, the carrier is anexcipient. Often, the pharmaceutically acceptable carrier is chemicallyinert toward the active compounds and is non-toxic under the conditionsof use. Examples of pharmaceutically acceptable carriers may include,for example, water or saline solution, polymers such as polyethyleneglycol, carbohydrates and derivatives thereof, oils, fatty acids, oralcohols. Non-limiting examples of oils as pharmaceutical carriersinclude oils of petroleum, animal, vegetable or synthetic origin, suchas peanut oil, soybean oil, mineral oil, sesame oil and the like. Thepharmaceutical carriers may also be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea, and the like. In addition,auxiliary, stabilizing, thickening, lubricating and coloring agents maybe used. Other examples of suitable pharmaceutical carriers aredescribed in e.g., Remington's: The Science and Practice of Pharmacy,22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); ModernPharmaceutics, 5^(th) Ed. (Alexander T. Florence, Juergen Siepmann, CRCPress (2009)); Handbook of Pharmaceutical Excipients, 7^(th) Ed. (Rowe,Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds.,Pharmaceutical Press (2012)) (each of which hereby incorporated byreference in its entirety).

In one embodiment, a pharmaceutical composition is a mixture of one ormore of the compounds described herein, or pharmaceutically acceptablesalts, solvates, pro-drugs or hydrates thereof, with other chemicalcomponents, such as physiologically acceptable carriers and excipients.The purpose of a pharmaceutical composition is to facilitateadministration of a compound to an organism or subject.

In another embodiment, the method of treatment, prevention and/orsuppression of a condition related to aldose reductase comprises thesteps of: (i) identifying a subject in need of such treatment; (ii)providing a compound of Formula (I), or a pharmaceutically acceptablesalt, solvate, hydrate or pro-drug thereof; or a composition comprisinga compound of Formula (I), or a pharmaceutically acceptable salt,solvate, hydrate or pro-drug thereof, and a pharmaceutically acceptablecarrier; and (iii) administering said compound or composition in atherapeutically effective amount to treat, prevent and/or suppress thedisease state or condition related to aldose reductase in a subject inneed of such treatment.

A “pro-drug” or “pro-drug” refers to an agent which is converted intothe active drug in vivo. Pro-drugs are often useful because, in somesituations, they are easier to administer than the parent drug. They arebioavailable, for instance, by oral administration whereas the parentdrug is either less bioavailable or not bioavailable. In someembodiments, the pro-drug has improved solubility in pharmaceuticalcompositions over the parent drug. For example, the compound carriesprotective groups that are removed in vivo, thus releasing activecompound. The term “pro-drug” may apply to such functionalities as, forexample, the acid functionalities of the compounds of Formula (I).Pro-drugs may be comprised of structures wherein an acid group ismasked, for example, as an ester or amide. Further examples of pro-drugsare discussed herein and, for example, by Alexander et al., J. Med.Chem. 1988, 31, 318 (hereby incorporated by reference in its entirety).

In one embodiment, the present invention also encompasses methodscomprising pro-drugs of compounds of Formula (I) and/or pharmaceuticalcompositions thereof. Pro-drugs include derivatives of compounds thatcan hydrolyze, oxidize, or otherwise react under biological conditions(in vitro or in vivo) to provide an active compound of the invention.Examples of pro-drugs include, but are not limited to, derivatives andmetabolites of a compound of the invention that include biohydrolyzablemoieties such as biohydrolyzable amides, biohydrolyzable esters,biohydrolyzable carbamates, biohydrolyzable carbonates, andbiohydrolyzable phosphate analogues. Pro-drugs may be comprised ofstructures wherein a acid group is masked, for example, as an ester oramide. Further examples of pro-drugs are discussed, for example, byAlexander et al., J. Med. Chem. 1988, 31, 318; and in The Practice ofMedicinal Chemistry (Camille Wermuth, ed., 1999, Academic Press; herebyincorporated by reference in its entirety). Pro-drugs are often usefulbecause, in some situations, they are easier to administer than theparent drug. They are bioavailable, for instance, by oral administrationwhereas the parent drug is either less bioavailable or not bioavailable.In some embodiments, the pro-drug has improved solubility inpharmaceutical compositions over the parent drug. For example, thecompound carries protective groups that are removed in vivo, thusreleasing active compound.

In certain embodiments, pro-drugs of compounds with carboxyl functionalgroups are the (C₁-C₄) alkyl esters of the carboxylic acid. Thecarboxylate esters are conveniently formed by esterifying any of thecarboxylic acid moieties present on the molecule. Pro-drugs cantypically be prepared using well-known methods, such as those describedby Burger's Medicinal Chemistry and Drug Discovery 6^(th) ed. (Donald J.Abraham ed., 2001, Wiley) and Design and Application of Pro-drugs (H.Bundgaard ed., 1985, Harwood Academic Publishers Gmfh; each of whichhereby incorporated by reference in its entirety). Biohydrolyzablemoieties of a compound of Formula (I) (i) do not interfere with thebiological activity of the compound but can confer upon that compoundadvantageous properties in vivo, such as uptake, duration of action, oronset of action; or (ii) may be biologically inactive but are convertedin vivo to the biologically active compound. Examples of biohydrolyzableesters include, but are not limited to, (C₁-C₄) alkyl esters,alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.Examples of biohydrolyzable amides include, but are not limited to,(C₁-C₄) alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamatesinclude, but are not limited to, (C₁-C₄) alkylamines, substitutedethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic andheteroaromatic amines, and polyether amines. In some embodiments, thebiohydrolyzable moiety is a (C₁-C₄) alkyl ester, an alkoxyacyloxy ester,an alkyl acylamino alkyl ester, or a choline ester. In some embodiments,the biohydrolyzable moiety is a (C₁-C₄) alkyl ester, an alkoxyacyloxyester, or an alkyl acylamino alkyl ester. In some embodiments, thebiohydrolyzable moiety is a (C₁-C₄) alkyl ester or an alkoxyacyloxyester. In some embodiments, the biohydrolyzable moiety is a (C₁-C₄)alkyl ester. In some embodiments, the biohydrolyzable moiety is a(C₁-C₃) alkyl ester. In some embodiments, the biohydrolyzable moiety isa methyl ester or an ethyl ester. In some embodiments, thebiohydrolyzable moiety is a t-butyl ester. In some embodiments, thebiohydrolyzable moiety is a (C₁-C₄) alkyl amide, an α-amino acid amide,an alkoxyacyl amide, or an alkylaminoalkylcarbonyl amide. In someembodiments, the biohydrolyzable moiety is a (C₁-C₄) alkyl amide, anα-amino acid amide, or an alkoxyacyl amide. In some embodiments, thebiohydrolyzable moiety is a (C₁-C₄) alkyl amide or an α-amino acidamide. In some embodiments, the biohydrolyzable moiety is a (C₁-C₄)alkyl amide.

In some embodiments, the biohydrolyzable moiety is a (C₁-C₄) alkylamine, a substituted ethylenediamine, an aminoacid, a hydroxyalkylamine,a heterocyclic amine, a heteroaromatic amine, or a polyether amine. Insome embodiments, the biohydrolyzable moiety is a (C₁-C₄) alkyl amine,an aminoacid, a hydroxyalkylamine, a heterocyclic amine, aheteroaromatic amine, or a polyether amine. In some embodiments, thebiohydrolyzable moiety is a (C₁-C₄) alkyl amine, an aminoacid, ahydroxyalkylamine, or a polyether amine. In some embodiments, thebiohydrolyzable moiety is a (C₁-C₄) alkyl amine, an aminoacid, or ahydroxyalkylamine. In some embodiments, the biohydrolyzable moiety is a(C₁-C₄) alkyl amine.

In one embodiment, the compounds of the invention are formulated intopharmaceutical compositions for administration to subjects in abiologically compatible form suitable for administration in vivo.According to another aspect, the present invention provides apharmaceutical composition comprising a compound of Formula (I) inadmixture with a pharmaceutically acceptable diluent and/or carrier. Thepharmaceutically-acceptable carrier is “acceptable” in the sense ofbeing compatible with the other ingredients of the composition and notdeleterious to the recipient thereof. The pharmaceutically-acceptablecarriers employed herein may be selected from various organic orinorganic materials that are used as materials for pharmaceuticalformulations and which are incorporated as analgesic agents, buffers,binders, disintegrants, diluents, emulsifiers, excipients, extenders,glidants, solubilizers, stabilizers, suspending agents, tonicity agents,vehicles and viscosity-increasing agents. Pharmaceutical additives, suchas antioxidants, aromatics, colorants, flavor-improving agents,preservatives, and sweeteners, may also be added. Examples of acceptablepharmaceutical carriers include carboxymethyl cellulose, crystallinecellulose, glycerin, gum arabic, lactose, magnesium stearate, methylcellulose, powders, saline, sodium alginate, sucrose, starch, talc andwater, among others. In one embodiment, the term “pharmaceuticallyacceptable” means approved by a regulatory agency of the Federal or astate government or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals, and more particularly inhumans.

Surfactants such as, for example, detergents, are also suitable for usein the formulations. Specific examples of surfactants includepolyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetateand of vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol,glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin orsodium carboxymethylcellulose; or acrylic derivatives, such asmethacrylates and others, anionic surfactants, such as alkalinestearates, in particular sodium, potassium or ammonium stearate; calciumstearate or triethanolamine stearate; alkyl sulfates, in particularsodium lauryl sulfate and sodium cetyl sulfate; sodiumdodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fattyacids, in particular those derived from coconut oil, cationicsurfactants, such as water-soluble quaternary ammonium salts of formulaN⁺R′R″R′″R″″Y⁻, in which the R radicals are identical or differentoptionally hydroxylated hydrocarbon radicals and Y⁻ is an anion of astrong acid, such as halide, sulfate and sulfonate anions;cetyltrimethylammonium bromide is one of the cationic surfactants whichcan be used, amine salts of formula N⁺R′R″R′″, in which the R radicalsare identical or different optionally hydroxylated hydrocarbon radicals;octadecylamine hydrochloride is one of the cationic surfactants whichcan be used, non-ionic surfactants, such as optionallypolyoxyethylenated esters of sorbitan, in particular Polysorbate 80, orpolyoxyethylenated alkyl ethers; polyethylene glycol stearate,polyoxyethylenated derivatives of castor oil, polyglycerol esters,polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids orcopolymers of ethylene oxide and of propylene oxide, amphotericsurfactants, such as substituted lauryl compounds of betaine.

When administered to a subject, the compound of Formula (I) andpharmaceutically acceptable carriers can be sterile. Suitablepharmaceutical carriers may also include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300,water, ethanol, polysorbate 20, and the like. The present compositions,if desired, may also contain minor amounts of wetting or emulsifyingagents, or pH buffering agents.

The pharmaceutical formulations of the present invention are prepared bymethods well-known in the pharmaceutical arts. Optionally, one or moreaccessory ingredients (e.g., buffers, flavoring agents, surface activeagents, and the like) also are added. The choice of carrier isdetermined by the solubility and chemical nature of the compounds,chosen route of administration and standard pharmaceutical practice.

Additionally, the compounds and/or compositions of the present inventionare administered to a human or animal subject by known proceduresincluding oral administration, sublingual or buccal administration. Inone embodiment, the compound and/or composition is administered orally.

For oral administration, a formulation of the compounds of the inventionmay be presented in dosage forms such as capsules, tablets, powders,granules, or as a suspension or solution. Capsule formulations may begelatin, soft-gel or solid. Tablets and capsule formulations may furthercontain one or more adjuvants, binders, diluents, disintegrants,excipients, fillers, or lubricants, each of which are known in the art.Examples of such include carbohydrates such as lactose or sucrose,dibasic calcium phosphate anhydrous, corn starch, mannitol, xylitol,cellulose or derivatives thereof, microcrystalline cellulose, gelatin,stearates, silicon dioxide, talc, sodium starch glycolate, acacia,flavoring agents, preservatives, buffering agents, disintegrants, andcolorants. Orally administered compositions may contain one or moreoptional agents such as, for example, sweetening agents such asfructose, aspartame or saccharin; flavoring agents such as peppermint,oil of wintergreen, or cherry; coloring agents; and preservative agents,to provide a pharmaceutically palatable preparation.

In some embodiments, the composition is in unit dose form such as atablet, capsule or single-dose vial. Suitable unit doses, i.e.,therapeutically effective amounts, may be determined during clinicaltrials designed appropriately for each of the conditions for whichadministration of a chosen compound is indicated and will, of course,vary depending on the desired clinical endpoint.

In accordance with the methods of the present invention, the compoundsof the invention are administered to the subject in a therapeuticallyeffective amount, for example to reduce or ameliorate symptoms relatedto aldose reductase activity in the subject. This amount is readilydetermined by the skilled artisan, based upon known procedures,including analysis of titration curves established in vivo and methodsand assays disclosed herein.

In one embodiment, the methods comprise administration of atherapeutically effective dosage of the compounds of the invention. Insome embodiments, the therapeutically effective dosage is at least about0.05 mg/kg body weight, at least about 0.1 mg/kg body weight, at leastabout 0.25 mg/kg body weight, at least about 0.3 mg/kg body weight, atleast about 0.5 mg/kg body weight, at least about 0.75 mg/kg bodyweight, at least about 1 mg/kg body weight, at least about 2 mg/kg bodyweight, at least about 3 mg/kg body weight, at least about 4 mg/kg bodyweight, at least about 5 mg/kg body weight, at least about 6 mg/kg bodyweight, at least about 7 mg/kg body weight, at least about 8 mg/kg bodyweight, at least about 9 mg/kg body weight, at least about 10 mg/kg bodyweight, at least about 15 mg/kg body weight, at least about 20 mg/kgbody weight, at least about 25 mg/kg body weight, at least about 30mg/kg body weight, at least about 40 mg/kg body weight, at least about50 mg/kg body weight, at least about 75 mg/kg body weight, at leastabout 100 mg/kg body weight, at least about 200 mg/kg body weight, atleast about 250 mg/kg body weight, at least about 300 mg/kg body weight,at least about 350 mg/kg body weight, at least about 400 mg/kg bodyweight, at least about 450 mg/kg body weight, at least about 500 mg/kgbody weight, at least about 550 mg/kg body weight, at least about 600mg/kg body weight, at least about 650 mg/kg body weight, at least about700 mg/kg body weight, at least about 750 mg/kg body weight, at leastabout 800 mg/kg body weight, at least about 900 mg/kg body weight, or atleast about 1000 mg/kg body weight. It will be recognized that any ofthe dosages listed herein may constitute an upper or lower dosage range,and may be combined with any other dosage to constitute a dosage rangecomprising an upper and lower limit.

In some embodiments, the methods comprise a single dosage oradministration (e.g., as a single injection or deposition).Alternatively, the methods comprise administration once daily, twicedaily, three times daily or four times daily to a subject in needthereof for a period of from about 2 to about 28 days, or from about 7to about 10 days, or from about 7 to about 15 days, or longer. In someembodiments, the methods comprise chronic administration. In yet otherembodiments, the methods comprise administration over the course ofseveral weeks, months, years or decades. In still other embodiments, themethods comprise administration over the course of several weeks. Instill other embodiments, the methods comprise administration over thecourse of several months. In still other embodiments, the methodscomprise administration over the course of several years. In still otherembodiments, the methods comprise administration over the course ofseveral decades.

The dosage administered can vary depending upon known factors such asthe pharmacodynamic characteristics of the active ingredient and itsmode and route of administration; time of administration of activeingredient; age, sex, health and weight of the recipient; nature andextent of symptoms; kind of concurrent treatment, frequency of treatmentand the effect desired; and rate of excretion. These are all readilydetermined and may be used by the skilled artisan to adjust or titratedosages and/or dosing regimens.

The precise dose to be employed in the compositions will also depend onthe route of administration, and should be decided according to thejudgment of the practitioner and each patient's circumstances. Inspecific embodiments of the invention, suitable dose ranges for oraladministration of the compounds of the invention are generally about 1mg/day to about 1000 mg/day. In one embodiment, the oral dose is about 1mg/day to about 800 mg/day. In one embodiment, the oral dose is about 1mg/day to about 500 mg/day. In another embodiment, the oral dose isabout 1 mg/day to about 250 mg/day. In another embodiment, the oral doseis about 1 mg/day to about 100 mg/day. In another embodiment, the oraldose is about 5 mg/day to about 50 mg/day. In another embodiment, theoral dose is about 5 mg/day. In another embodiment, the oral dose isabout 10 mg/day. In another embodiment, the oral dose is about 20mg/day. In another embodiment, the oral dose is about 30 mg/day. Inanother embodiment, the oral dose is about 40 mg/day. In anotherembodiment, the oral dose is about 50 mg/day. In another embodiment, theoral dose is about 60 mg/day. In another embodiment, the oral dose isabout 70 mg/day. In another embodiment, the oral dose is about 100mg/day. It will be recognized that any of the dosages listed herein mayconstitute an upper or lower dosage range, and may be combined with anyother dosage to constitute a dosage range comprising an upper and lowerlimit.

Any of the compounds and/or compositions of the invention may beprovided in a kit comprising the compounds and/or compositions. Thus, inone embodiment, the compound and/or composition of the invention isprovided in a kit.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be within the scope of the present invention.

The invention is further described by the following non-limitingExamples.

EXAMPLES

Examples are provided below to facilitate a more complete understandingof the invention. The following examples serve to illustrate theexemplary modes of making and practicing the invention. However, thescope of the invention is not to be construed as limited to specificembodiments disclosed in these Examples, which are illustrative only.

Example 1: Preparation of Compound VII

Compound VII was prepared as schematically illustrated below.

2-(chloromethyl)-5-(trifluoromethyl)benzo[d]thiazole (Compound I-S)

Compound I-S was prepared using the same method described previously inU.S. Pat. No. 8,916,563.

4,6-dichloro-1H,3H-thieno[3,4-c]furan-1,3-dione (Compound II)

Compound II was prepared using the same method described previous inAyres, B. E., Longworth, S. W., McOmie, J. F. W. Tetrahedron, 1975, 31,1755-1760.

2,5-dichloro-4-(methoxycarbonyl)thiophene-3-carboxylic Acid (CompoundIII)

A solution of 0.495 g (2.22 mmol) of4,6-dichloro-1H,3H-thieno[3,4-c]furan-1,3-dione (Compound II) in 4.0 mLof MeOH was treated with TFA (1 drop) and heated to 65° C. overnight.The reaction mixture was cooled to ambient temperature and concentratedin vacuo. To the obtained residue was added ether followed by saturatedaqueous NaHCO₃. The layers were separated and the aqueous layer wasextracted with ether (1×). The aqueous layer was then acidified to pH=2by addition of conc. HCl. The aqueous layer was extracted with EtOAc(3×) and the combined organics from the second extraction washed withbrine (1×). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo to yield 0.537 g (95% crude yield) of2,5-dichloro-4-(methoxycarbonyl)thiophene-3-carboxylic acid (CompoundIII) as a white solid that was used without further purification: ¹H NMR(CDCl₃, 400 MHz): δ_(ppm) 3.91 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz):δ_(ppm) 165.6, 162.0, 133.9, 131.0, 129.6, 128.1, 53.0.

Methyl4-(3-(tert-butoxy)-3-oxopropanoyl)-2,5-dichlorothiophene-3-carboxylate(Compound IV)

In a first flask, a solution of 0.537 g (2.11 mmol) of Compound III in8.0 mL of DMF was treated slowly with 0.393 g (2.42 mmol) of CDI. Thereaction mixture was stirred at ambient temperature for 2 hours. In aseparate second flask, to a solution of 0.439 g (2.74 mmol) ofmono-tert-butyl malonate in 8.0 mL of DMF cooled to 0° C. was added0.261 g (2.74 mmol) of MgCl₂. After stirring at 0° C. for 5 minutes, 1.2mL (8.42 mmol) of triethylamine was added and the resulting reactionmixture stirred at ambient temperature for 2 hours. After 2 hours, thecontent of flask #1 was added to flask #2 and the combined reactionmixture stirred at ambient temperature overnight. Subsequently, thereaction mixture was cooled to 0° C. and treated with aqueous 1.0 M HCland stirred for 20 minutes. The mixture was extracted with ether (3×)and washed sequentially with water (2×) and brine (1×). The organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo to yieldcrude material 0.170 g (23% crude yield) of methyl4-(3-(tert-butoxy)-3-oxopropanoyl)-2,5-dichlorothiophene-3-carboxylate(Compound IV) that was used without further purification.

Tert-butyl2-(5,7-dichloro-4-oxo-3,4-dihydrothieno[3,4-c]pyridazin-1-yl)acetate(Compound V)

To 0.170 g (0.482 mmol) of Compound IV in 4.0 mL of MeOH was added 17 μL(0.530 mmol) of hydrazine. The resulting reaction mixture was stirred atambient temperature for 2 hours. Subsequently, the reaction mixture wasconcentrated in vacuo and the residue purified via flash columnchromatography over silica gel (monitored by thin layer chromatography)and eluted with 2:1 (v/v) hexanes:ethyl acetate. Evaporation of thecollected fractions yielded 0.091 g (57% yield) of tert-butyl2-(5,7-dichloro-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate(Compound V) as a white solid: ¹H NMR (CDCl₃, 400 MHz): δ_(ppm) 9.15 (brs, 1H), 3.89 (s, 2H), 1.46 (s, 9H).

Tert-butyl2-(5,7-dichloro-4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-c]pyridazin-1-yl)acetate(Compound VI)

To a solution of 0.091 g (0.271 mmol) of Compound V in 3.0 mL of DMF wasadded 0.037 g (0.326 mmol) of KO^(t)Bu. The resulting dark mixture wasstirred at ambient temperature for 10 minutes before 0.082 g (0.326mmol) of 2-(chloromethyl)-5-(trifluoromethyl)benzo[d]thiazole (CompoundI-S) was added. After the reaction mixture stirred at ambienttemperature for 2 hours, the reaction mixture was partitioned betweenwater and ether, the layers separated, and the aqueous layer extractedwith ether (2×). The combined ethereal layers were washed sequentiallywith saturated aqueous NaHCO₃ (1×), water (1×), 1.0M aqueous HCl (1×),and brine (1×). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The obtained residue was purified via flashcolumn chromatography over silica gel (monitored by thin layerchromatography) and eluted with 4:1 (v/v) hexanes:ethyl acetate.Evaporation of the collected fractions yielded 0.072 g (48% yield) oftert-butyl2-(5,7-dichloro-4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate(Compound VI): ¹H NMR (CDCl₃, 400 MHz): δ_(ppm) 8.28 (s, 1H), 7.94 (d,J=8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 5.63 (s, 2H), 3.92 (s, 2H), 1.45(s, 9H); MS ESI (m/z) 550 (M+1)⁺.

2-(5,7-dichloro-4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)aceticAcid (Compound VII)

To a solution of 0.072 g (0.131 mmol) of Compound VI in 1.0 mL of THFwas added 5.0 mL of formic acid (88% in water) and 0.5 mL of water. Thereaction mixture was stirred for 12 hours at ambient temperature. Thereaction mixture was concentrated in vacuo and the residue partitionedbetween ether and saturated aqueous NaHCO₃. The layers were separatedand the aqueous layer acidified to pH 2 by addition of conc. HCl. Theprecipitated solid was collected via filtration to yield 8 mg (12%yield) of2-(5,7-dichloro-4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)aceticacid (Compound VII) as a white solid: m.p.=205-207° C. (notrecrystallized); ¹H NMR (acetone, 400 MHz): δ_(ppm) 8.32-8.28 (m, 2H),7.75 (d, J=7.6 Hz, 1H), 5.67 (s, 2H), 4.04 (s, 2H); MS ESI (m/z) 494(M+1)⁺.

Example 2: Preparation of Compound XII

Compound XII was prepared as schematically illustrated below.

4-(methoxycarbonyl)thiophene-3-carboxylic Acid (Compound VIII)

Compound VIII was prepared using the same method described previous inHawker, D. D., Silverman, R. B. Bioorg. Med. Chem., 2012, 20, 5763-5773.

Methyl 4-(3-(tert-butoxy)-3-oxopropanoyl)thiophene-3-carboxylate(Compound IX)

In a first flask, a solution of 5.27 g (28.31 mmol) of Compound VIII in35 mL of NMP was treated slowly with 5.28 g (32.55 mmol) of CDI. Thereaction mixture was stirred at ambient temperature for 2 hours. In aseparate second flask, to a solution of 5.67 g (35.39 mmol) ofmono-tert-butyl malonate in 50 mL of NMP cooled to 0° C. was added 3.37g (35.39 mmol) of MgCl₂. After stirring at 0° C. for 5 minutes, 14.8 mL(84.93 mmol) of N,N-diisopropylethylamine was added and the resultingreaction mixture stirred at ambient temperature for 2 hours. After 2hours, the content of flask #1 was added to flask #2 and the combinedreaction mixture stirred at ambient temperature overnight. Subsequently,the reaction mixture was cooled to 0° C. and treated with aqueous 1.0 MHCl and stirred for 20 minutes. The mixture was extracted with ether(3×) and washed sequentially with water (2×) and brine (1×). The organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was dissolved in 10 mL of ethyl acetate and 110 mL of hexaneswas added. Stirred for 10 minutes and the solid precipitate was filteredoff. Concentrated the filtrate in vacuo and the crude methyl4-(3-(tert-butoxy)-3-oxopropanoyl)thiophene-3-carboxylate (Compound IX)was carried on without further purification.

Tert-butyl 2-(4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate(Compound X)

To a solution of 8.04 g (28.31 mmol) of crude Compound IX in 70 mL ofMeOH at 0° C. was added 2.7 mL (42.46 mmol) of hydrazine hydrate (50-60%in H₂O). The resulting reaction mixture was stirred at 0° C. for 2hours. Diluted the reaction mixture with water and the precipitatedsolid was collected via filtration to yield 2.99 g (40% yield over twosteps) of tert-butyl2-(4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound X) asa white solid: ¹H NMR (CDCl₃, 400 MHz): δ_(ppm) 9.29 (br s, 1H), 8.44(d, J=2.4 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 3.76 (s, 2H), 1.44 (s, 9H);¹³C NMR (CDCl₃, 100 MHz): δ_(ppm) 168.5, 158.0, 139.2, 133.3, 130.7,129.3, 123.9, 82.1, 40.9, 27.9; ESI (m/z) 308 (M+MeCN)⁺.

Tert-butyl2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-c]pyridazin-1-yl)acetate(Compound XI)

To a solution of 0.100 g (0.376 mmol) of Compound X in 2.5 mL of DMF wasadded 0.044 g (0.391 mmol) of KOtBu. The resulting dark mixture wasstirred at ambient temperature for 15 minutes before 0.104 g (0.414mmol) of Compound I-S was added. After the reaction mixture stirred atambient temperature for 2 hours, the reaction mixture was partitionedbetween water and ether, the layers separated, and the aqueous layerextracted with ether (2×). The combined ethereal layers were washedsequentially with 1.0M NaOH (1×), water (1×), 1.0M aqueous HCl (1×), andbrine (1×). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The obtained residue was purified via flashcolumn chromatography over silica gel (monitored by thin layerchromatography) and eluted with 2:1 (v/v) hexanes:ethyl acetate.Evaporation of the collected fractions yielded 0.058 g (32% yield) oftert-butyl2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate(Compound XI): ¹H NMR (CDCl₃, 400 MHz): δ_(ppm) 8.45 (d, J=3.2 Hz, 1H),8.29 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.83 (d, J=3.2 Hz, 1H), 7.59 (d,J=8.8 Hz, 1H), 5.75 (s, 2H), 3.78 (s, 2H), 1.41 (s, 9H); ESI (m/z) 482(M+H)⁺.

2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)aceticAcid (Compound XII)

A solution of 0.058 g (0.121 mmol) of Compound XI in 1.0 mL oftrifluoroacetic acid and 1.0 mL of CH₂Cl₂ was stirred at ambienttemperature for 2 hours. The reaction mixture was concentrated in vacuoand the residue partitioned between ether and saturated aqueous NaHCO₃.The layers were separated and the ethereal layer washed with saturatedaqueous NaHCO₃ (1×). The aqueous layer was acidified to pH=2 by additionof conc. HCl and the precipitated solid was collected via filtration toyield 20 mg (39% yield) of2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)aceticacid (Compound XII) as a white solid: m.p.=174-176° C. (notrecrystallized); ¹H NMR (acetone, 400 MHz): δ_(ppm) 8.60 (d, J=3.2 Hz,1H), 8.33 (d, J=3.2 Hz, 1H), 8.29 (s, 1H), 8.26 (d, J=8.8 Hz, 1H), 7.74(d, J=8.8 Hz, 1H), 5.74 (s, 2H), 3.96 (s, 2H); MS ESI (m/z) 426 (M+1)⁺.

Example 3: Preparation of Compound XIII

Compound XIII, shown above, was prepared as follows: The preparationdescribed for Compound XI was repeated except that2-(bromomethyl)-5-fluorobenzo[d]thiazole was the reagent employed inplace of Compound I-S using the same molar proportions as before. Inthis case, the final product obtained was tert-butyl2-(3-((5-fluorobenzo[d]thiazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate(Compound XIII) that was carried on crude after filtering over a plug ofsilica washing with 2:1 (v/v) hexanes:ethyl acetate

Example 4: Preparation of Compound XIV

Compound XIV, shown above, was prepared as follows: The preparationdescribed for Compound XII was repeated except that Compound XIII wasthe starting material employed in place of Compound XI. In this case,the final product obtained was2-(3-((5-fluorobenzo[d]thiazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)aceticacid (Compound XIV) in 25% yield: m.p.=172-173° C. (not recrystallized);¹H NMR (CDCl₃, 400 MHz): δ_(ppm) 8.47 (d, J=3.2 Hz, 1H), 7.85 (d, J=3.2Hz, 1H), 7.75-7.69 (m, 2H), 7.13 (dt, J=8.8, 2.8 Hz, 1H), 5.72 (s, 2H),3.93 (s, 2H); ESI (m/z) 376 (M+H)⁺.

Example 5: Preparation of Compound XV

Compound XV, shown above, was prepared as follows: The preparationdescribed for Compound XI was repeated except that2-(bromomethyl)benzo[d]thiazole was the reagent employed in place ofCompound I-S using the same molar proportions as before. In this case,the final product obtained was tert-butyl2-(3-(benzo[d]thiazol-2-ylmethyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate(Compound XV) that was carried on crude after filtering over a plug ofsilica washing with 3:1 (v/v) hexanes:ethyl acetate.

Example 6: Preparation of Compound XVI

Compound XVI, shown above, was prepared as follows: The preparationdescribed for Compound XII was repeated except that Compound XV was thestarting material employed in place of Compound XI. In this case, thefinal product obtained was2-(3-(benzo[d]thiazol-2-ylmethyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)aceticacid (Compound XVI) in 7% yield: m.p.=172-173° C. (not recrystallized);¹H NMR (acetone, 400 MHz): δ_(ppm) 8.58 (d, J=2.8 Hz, 1H), 8.30 (d,J=2.8 Hz, 1H), 7.99-7.94 (m, 2H), 7.49 (t, J=8.0 Hz, 1H), 7.41 (t, J=8.0Hz, 1H), 5.68 (s, 2H), 3.94 (s, 2H); ESI (m/z) 358 (M+H)⁺.

Example 7: Preparation of Compound XVII

Compound XVII, shown above, was prepared as follows: The preparationdescribed for Compound XI was repeated except that3-(bromomethyl)-5-chlorobenzo[b]thiophene was the reagent employed inplace of Compound I-S using the same molar proportions as before. Inthis case, the final product obtained was tert-butyl2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate(Compound XVII). The obtained product was purified via flash columnchromatography over silica gel (monitored by thin layer chromatography)and eluted with 3:1 (v/v) hexanes:ethyl acetate. Evaporation of thecollected fractions yielded 18% yield of Compound XVII: ¹H NMR (CDCl₃,400 MHz): δ_(ppm) 8.38 (d, J=3.2 Hz, 1H), 8.19 (d, J=1.2 Hz, 1H), 7.75(d, J=3.2 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.58 (s, 1H), 7.30-7.27 (m,1H), 5.48 (s, 2H), 3.76 (s, 2H), 1.40 (s, 9H); ESI (m/z) 447 (M+H)⁺.

Example 8: Preparation of Compound XVIII

Compound XVIII, shown above, was prepared as follows: The preparationdescribed for Compound XII was repeated except that Compound XVII wasthe starting material employed in place of Compound XI. In this case,the final product obtained was2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)aceticacid (Compound XVIII) in 25% yield: ¹H NMR (acetone, 400 MHz): δ_(ppm)8.53 (d, J=2.8 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 8.23 (d, J=2.8 Hz, 1H),7.95 (d, J=8.8 Hz, 1H), 7.75 (s, 1H), 7.37 (dd, J=8.8, 2.0 Hz, 1H), 5.51(s, 2H), 3.92 (s, 2H); ESI (m/z) 391 (M+H)⁺, 389 (M−H)⁻.

Example 9: Preparation of Compound XIX

Compound XIX, shown above, was prepared as follows: The preparationdescribed for Compound XI was repeated except that5-chloro-2-(chloromethyl)benzo[d]thiazole was the reagent employed inplace of Compound I-S using the same molar proportions as before. Inthis case, the final product obtained was tert-butyl2-(3-((5-chlorobenzo[d]thiazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate(Compound XIX). The obtained product was purified via flash columnchromatography over silica gel (monitored by thin layer chromatography)and eluted with 4:1 (v/v) hexanes:ethyl acetate. Evaporation of thecollected fractions yielded 47% yield of Compound XIX: ¹H NMR (CDCl₃,400 MHz): δ_(ppm) 8.44 (d, J=3.2 Hz, 1H), 8.00 (s, 1H), 7.82 (d, J=3.2Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 5.72 (s, 2H),3.77 (s, 2H), 1.40 (s, 9H); ESI (m/z) 448 (M+H)⁺.

Example 10: Preparation of Compound XX

Compound XX, shown above, was prepared as follows: The preparationdescribed for Compound XII was repeated except that Compound XIX was thestarting material employed in place of Compound XI. In this case, thefinal product obtained was2-(3-((5-chlorobenzo[d]thiazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)aceticacid (Compound XX) in 61% yield: m.p.=184-185° C. (not recrystallized);¹H NMR (acetone, 400 MHz): δ_(ppm) 8.59 (d, J=2.8 Hz, 1H), 8.32 (d,J=2.8 Hz, 1H), 8.03-7.99 (m, 2H), 7.45 (d, J=8.8 Hz, 1H), 5.69 (s, 2H),3.95 (s, 2H); ESI (m/z) 392 (M+H)⁺.

Example 11: Preparation of Compound XXI

Compound XXI, shown above, was prepared as follows: The preparationdescribed for Compound XI was repeated except that2-(chloromethyl)-6-fluorobenzo[d]oxazole was the reagent employed inplace of Compound I-S using the same molar proportions as before. Inthis case, the final product obtained was tert-butyl2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate(Compound XXI). The obtained product was purified via flash columnchromatography over silica gel (monitored by thin layer chromatography)and eluted with 4:1 (v/v) hexanes:ethyl acetate. Evaporation of thecollected fractions yielded 30% yield of Compound XXI: ¹H NMR (CDCl₃,400 MHz): δ_(ppm) 8.44 (d, J=3.2 Hz, 1H), 7.81 (d, J=3.2 Hz, 1H), 7.60(dd, J=8.8, 4.8 Hz, 1H), 7.19 (dd, J=7.6, 2.0 Hz, 1H), 7.05 (dt, J=8.8,2.0 Hz, 1H), 5.58 (s, 2H), 3.75 (s, 2H), 1.40 (s, 9H); ESI (m/z) 416(M+H)⁺.

Example 12: Preparation of Compound XXII

Compound XXII, shown above, was prepared as follows: The preparationdescribed for Compound XII was repeated except that Compound XXI was thestarting material employed in place of Compound XI. In this case, thefinal product obtained was2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)aceticacid (Compound XXII) in 40% yield: ¹H NMR (acetone, 400 MHz): δ_(ppm)8.57 (d, J=3.2 Hz, 1H), 8.30 (d, J=3.2 Hz, 1H), 7.65 (dd, J=8.8, 5.2 Hz,1H), 7.45 (dd, J=8.0, 2.4 Hz, 1H), 7.17 (dt, J=8.8, 2.4 Hz, 1H), 5.57(s, 2H), 3.91 (s, 2H); ESI (m/z) 360 (M+H)⁺.

Example 13: Preparation of Compound XXIII

Compound XXIII, shown above, was prepared as follows: The preparationdescribed for Compound XI was repeated except that5-chloro-2-(chloromethyl)benzofuran was the reagent employed in place ofCompound I-S using the same molar proportions as before. In this case,the final product obtained was tert-butyl2-(3-((5-chlorobenzofuran-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate(Compound XXIII) The obtained product was purified via flash columnchromatography over silica gel (monitored by thin layer chromatography)and eluted with 2:1 (v/v) hexanes:ethyl acetate. Evaporation of thecollected fractions yielded 33% yield of Compound XXIII: m.p.=117-118°C. (not recrystallized); ¹H NMR (CDCl₃, 400 MHz): δ_(ppm) 8.40 (d, J=3.2Hz, 1H), 7.78 (d, J=3.2 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.33 (d, J=8.4Hz, 1H), 7.17 (dd, J=8.4, 2.4 Hz, 1H), 6.65 (s, 1H), 5.44 (s, 2H), 3.76(s, 2H), 1.41 (s, 9H); ESI (m/z) 431 (M+H)⁺.

Example 14: Preparation of Compound XXIV

Compound XXIV, shown above, was prepared as follows: The preparationdescribed for Compound XII was repeated except that Compound XXIII wasthe starting material employed in place of Compound XI. In this case,the final product obtained was2-(3-((5-chlorobenzofuran-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)aceticacid (Compound XXIV) in 54% yield: m.p.=154-155° C. (notrecrystallized); ¹H NMR (acetone, 400 MHz): δ_(ppm) 8.54 (d, J=3.2 Hz,1H), 8.26 (d, J=3.2 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.47 (d, J=8.8 Hz,1H), 7.26 (dd, J=8.8, 2.0 Hz, 1H), 6.77 (s, 1H), 5.44 (s, 2H), 3.91 (s,2H); ESI (m/z) 375 (M+H)⁺.

Example 15: Preparation of Compound XXV

Compound XXV, shown above, was prepared as follows: The preparationdescribed for Compound XI was repeated except that2-(chloromethyl)benzofuran was the reagent employed in place of CompoundI-S using the same molar proportions as before. In this case, the finalproduct obtained was tert-butyl2-(3-(benzofuran-2-ylmethyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate(Compound XXV). The obtained product was purified via flash columnchromatography over silica gel (monitored by thin layer chromatography)and eluted with 2:1 (v/v) hexanes:ethyl acetate. Evaporation of thecollected fractions yielded 44% yield of Compound XXV: ¹H NMR (CDCl₃,400 MHz): δ_(ppm) 8.40 (d, J=3.2 Hz, 1H), 7.76 (d, J=3.2 Hz, 1H), 7.48(d, J=7.6 Hz, 1H), 7.41 (d, J=8.0, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.17 (t,J=7.6 Hz, 1H), 6.70 (s, 1H), 5.45 (s, 2H), 3.76 (s, 2H), 1.40 (s, 9H);ESI (m/z) 397 (M+H)⁺.

Example 16: Preparation of Compound XXVI

Compound XXVI, shown above, was prepared as follows: The preparationdescribed for Compound XII was repeated except that Compound XXV was thestarting material employed in place of Compound XI. In this case, thefinal product obtained was2-(3-(benzofuran-2-ylmethyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)aceticacid (Compound XXVI) in 28% yield: m.p.=158-159° C. (notrecrystallized); ¹H NMR (acetone, 400 MHz): δ_(ppm) 8.54 (d, J=3.2 Hz,1H), 8.26 (d, J=3.2 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.45 (d, J=8.4 Hz,1H), 7.26 (t, J=8.4 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 6.76 (s, 1H), 5.44(s, 2H), 3.91 (s, 2H); ESI (m/z) 341 (M+H)⁺.

Example 17: Physical, Chemical, and Biological Assay Methods and Results

Characterization of Aldose Reductase Inhibitor Compounds:

The compounds were synthesized as summarized previously and werecharacterized in terms of physical characteristics (solubility and LogD) as well as biochemically in terms of ability to inhibit AldoseReductase enzymatic activity in vitro. Methods for these assays andresults are summarized below.

Equilibrium Solubility in Phosphate Buffer, pH 7.4:

The equilibrium solubility of test articles was measured in pH 7.4aqueous buffers. The pH 7.4 buffer was prepared by combining 50 mL of0.2 M KH₂PO₄ with 150 mL of H₂O, and then adjusting to pH 7.4 with 10 NNaOH. At least 1 mg of powder for each test article was combined with 1mL of buffer to make a ≥1 mg/mL mixture. These samples were shaken on aThermomixer® overnight at room temperature. The samples were thencentrifuged for 10 minutes at 10,000 rpm. The supernatant was sampledand diluted in duplicate 10-fold, 100-fold, and 10,000-fold into amixture of 1:1 buffer:acetonitrile (ACN) prior to analysis. All sampleswere assayed by LC-MS/MS using electrospray ionization against standardsprepared in a mixture of 1:1 assay buffer:ACN. Standard concentrationsranged from 1.0 μM to 1.0 nM.

Octanol/Buffer Partition Coefficient (Log D) at pH 7.4:

The octanol/buffer partition coefficient of three test articles wasmeasured at pH 7.4. The pH 7.4 buffer was prepared by combining 50 mL of0.2 M solution of KH₂PO₄ with 150 mL of dH₂O, and then adjusting to pH7.4 with 10 N NaOH. In a single incubation, 15 μL of a 10 mM DMSOsolution of each test article (100 μM) was added to test tubes whichcontained 0.75 mL of octanol and 0.75 mL of pH 7.4 phosphate buffer.Testosterone was also introduced to each tube as an internal control,also at a dosing concentration of 100 μM. These samples were gentlymixed on a benchtop rotator for 1 hour at room temperature. The tubeswere then removed from the rotator and the aqueous and organic phaseswere allowed to separate for 1 hour. An aliquot of the organic layer wastaken and diluted 200-fold into a mixture of 1:1 buffer:acetonitrile(ACN). An aliquot of the aqueous layer was taken and diluted 2-fold,10-fold, and 200-fold into a mixture of 1:1 buffer:ACN. All samples wereassayed by LC-MS/MS using electrospray ionization. Testosterone wasutilized as a positive control (with a published/known Log D of3.0-3.4).

Aldose Reductase Enzymatic Inhibition:

All compounds and Zopolrestat were tested individually in a micro plateassay for AR inhibition using D-glyceraldehyde and NADPH as substrateand the absorbance changes at 340 nm was monitored. % Inhibition wascalculated for ARIs at concentration ranging 0.1 nm to 10 uM. Theenzymatic inhibition assay was performed as described in WO 2012/009553,which is hereby incorporated by reference in its entirety.

TABLE 1 Physical, Chemical, and Biological Assay Results: Aldose Mol.Solu- Reductase Wt. bility Inhibition Compound Structure (AMU) (mg/mL)LogD (IC50) XIV

375 0.65 −0.87 60 nm VI

357 0.81 −1.01 190 nM XX

391 0.59 −0.35 35 nM XII

425 0.97 −0.09 0.1 nM XXVI

340 0.79 −0.86 57 nM XIV

374 0.76 −0.01 64 nM

Although the invention has been described and illustrated in theforegoing illustrative embodiments, it is understood that the presentdisclosure has been made only by way of example, and that numerouschanges in the details of implementation of the invention can be madewithout departing from the spirit and scope of the invention, which islimited only by the claims that follow. Features of the disclosedembodiments can be combined and rearranged in various ways within thescope and spirit of the invention.

What is claimed is:
 1. A compound of Formula (I)

wherein, R¹ is CO₂R²; R² is H, (C₁-C₆)-alkyl, (C₁-C₆)-hydroxyalkyl, or(C₁-C₆)-aminoalkyl; X¹ is H; X² is H; Y is C═O; Z is

A¹ is S; A² is N; and R³ through R⁶ are independently hydrogen, halogen,cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl,(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio, (C₁-C₄)-alkylsulfinyl,or (C₁-C₄)-alkyl sulfonyl; or a pharmaceutically acceptable salt orsolvate thereof.
 2. The compound of claim 1, wherein R² is(C₁-C₆)-alkyl.
 3. The compound of claim 2, wherein R³ through R⁶ areindependently hydrogen, halogen, or haloalkyl.
 4. The compound of claim1, wherein R¹ is (C₁-C₆)-hydroxyalkyl.
 5. The compound of claim 4,wherein R³ through R⁶ are independently hydrogen, halogen, or haloalkyl.6. The compound of claim 1, wherein R¹ is (C₁-C₆)-aminoalkyl.
 7. Thecompound of claim 6, wherein R³ through R⁶ are independently hydrogen,halogen, or haloalkyl.
 8. The compound of claim 1, wherein R² is H. 9.The compound of claim 8, wherein R³ through R⁶ are independentlyhydrogen, halogen, or haloalkyl.
 10. The compound of claim 1, whereinR³, R⁵ and R⁶ are each hydrogen; and R⁴ is hydrogen, halogen, orhaloalkyl.
 11. The compound of claim 2, wherein R³, R⁵ and R⁶ are eachhydrogen; and R⁴ is hydrogen, halogen, or haloalkyl.
 12. The compound ofclaim 4, wherein R³, R⁵ and R⁶ are each hydrogen; and R⁴ is hydrogen,halogen, or haloalkyl.
 13. The compound of claim 6, wherein R³, R⁵ andR⁶ are each hydrogen; and R⁴ is hydrogen, halogen, or haloalkyl.
 14. Thecompound of claim 8, wherein R³, R⁵ and R⁶ are each hydrogen; and R⁴ ishydrogen, halogen, or haloalkyl.
 15. The compound

or a pharmaceutically acceptable salt or solvate thereof.
 16. Thecompound

or a pharmaceutically acceptable salt or solvate thereof.
 17. Thecompound

or a pharmaceutically acceptable salt or solvate thereof.
 18. Thecompound

or a pharmaceutically acceptable salt or solvate thereof.
 19. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 20. A pharmaceutical compositioncomprising a compound of claim 15 and a pharmaceutically acceptablecarrier.
 21. A pharmaceutical composition comprising a compound of claim16 and a pharmaceutically acceptable carrier.
 22. A pharmaceuticalcomposition comprising a compound of claim 17 and a pharmaceuticallyacceptable carrier.
 23. A pharmaceutical composition comprising acompound of claim 18 and a pharmaceutically acceptable carrier.